Is TCN2 p.Ser53= (c.159C>T) pathogenic?

TCN2 p.Ser53= (c.159C>T) is classified Likely benign in TCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-09). Ultra-rare (popmax 0.0132%, sas); Associated with transcobalamin II deficiency.

What condition is associated with TCN2 p.Ser53= (c.159C>T)?

TCN2 p.Ser53= (c.159C>T) is associated with transcobalamin II deficiency (ClinVar).

How common is TCN2 p.Ser53= (c.159C>T) in the general population?

TCN2 p.Ser53= (c.159C>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

How is Transcobalamin deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TCN2 p.Ser53=

c.159C>T · rs771569755 · VCV2154707

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Conditions

transcobalamin II deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.84	GERP 0.6, phastCons 0.43
Overall
CADD	8.201	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% South Asian · 12/91,090 alleles

Filtering AF 0.0075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.000867% 14/1,614,218 alleles · ultra-rare exomes 14/1,461,888 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,591
Remaining individualsnot grpmax-eligible	0.0032%	31,254

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TCN2
Protein: p.Ser53=
Coding: c.159C>T
MANE Select: NM_000355
dbSNP: rs771569755
Type: single nucleotide variant
Location: chr22:30610965 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.76 · 11 PDB
Residue 53: an α-helix

Full TCN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

transcobalamin II deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Transcobalamin deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TCN2 c.1106+1G>A Pathogenic ★★ same condition
TCN2 c.428-2A>G Pathogenic/Likely pathogenic ★★ same condition
TCN2 p.Arg227Ter Pathogenic/Likely pathogenic ★★ same condition
TCN2 p.Gln188Ter Pathogenic/Likely pathogenic ★★ same condition
TCN2 p.Gln291Ter Pathogenic ★★ same condition
TCN2 p.Gly367Ter Pathogenic/Likely pathogenic ★★ same condition
TCN2 c.753+5G>A Uncertain significance ★★ same condition
TCN2 p.Ala261Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tcn2-p-ser53 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown